The invention relates to methods and compositions for the percutaneous delivery of opioid analgesics through the epidermis and, more specifically, to methods and compositions for the percutaneous delivery of loperamide hydrochloride through the epidermis.
Opioid analgesics such as morphine are known for the ability to relieve pain. This pharmacological effect occurs in at least three ways: (1) reduction of the central perception of pain probably at the thalamic level, (2) alteration of the reaction to pain probably at the level of the cerebral cortex, and (3) elevation of the pain threshold by inducing sedation or sleep.
Certain opioids are also known to be antihyperalgesic. As an antihyperalgesic opioid, loperamide hydrochloride is effective in treating pain and hypersensitivity to painful stimuli associated with inflammatory skin conditions. Due to its high affinity for peripheral opioid receptors and poor ability to penetrate the central nervous system, loperamide hydrochloride is an excellent candidate for topical administration of an antihyperalgesic.
The Merck index (Twelfth Edition, Merck and Co., Inc., Whitehouse Station, N.J., 1996) presents the solubility of loperamide hydrochloride in a variety of solvents, stated as grams per 100 mL solvent. The stated values are: water (at physiological pH) 0.002; water (pH 1.7) 0.14; citrate-phosphate buffer (pH 6.1) 0.008; citrate-phosphate buffer (pH 7.9) less than 0.001; methanol 28.6; ethanol 5.37; 2-propanol 1.11; dichloromethane 35.1; acetone 0.20; ethyl acetate 0.035; diethyl ether less than 0.001; hexane less than 0.001; toluene 0.001; N,N-dimethylformamide 10.3; tetrahydrofuran 0.32; 4-methyl-2-pentanone 0.020; propylene glycol 5.64; polyethylene glycol 400 1.40; dimethylsulfoxide 20.5; 2-butanone 0.18.
U.S. Pat. No. 5,116,847 (issued May 26, 1992) describes compositions and methods for the treatment of respiratory disease symptoms. An array of chemical structures are disclosed, including loperamide, loperamide salts, and loperamide N-oxides. Compositions for nasal administration include aqueous benzalkonium chloride, thimerosal, or phenylmercuric acetate.
U.S. Pat. No. 5,667,773 (issued Sep. 16, 1997) describes topical anti-hyperalgesic compositions comprising one of an array of chemical compounds. The compositions further comprise a film-forming polymer material and an aqueous pharmaceutically acceptable carrier. The chemical compounds include loperamide.
Osborne and Henke (Pharm. Technol. 58-66, November 1997) discusses skin penetration enhancers cited in the technical literature for the transdermal delivery of pharmaceuticals.
Roberts and Walters (xe2x80x9cDermal Absorption and Toxicity Assessmentxe2x80x9d, Marcel Dekker, Inc., New York, 1998) and Osborne and Amann (xe2x80x9cTopical Drug Delivery Formulationsxe2x80x9d, Marcel Dekker, Inc., New York, 1990) are general texts teaching the topical administration of pharmaceuticals and cosmetics.
There exists a need for improved compositions and topical administration methods for opioid analgesics generally, and for loperamide hydrochloride in particular.
An effective dermal algesic or antihyperalgesic composition would comprise an opioid and a vehicle for delivering the opioid into the skin. There are numerous obstacles to achieving such a composition.
The primary obstacle for topical administration of pharmaceuticals is to deliver a topically-applied substance through the stratum corneum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids as well as living cells. Applicants have discovered a second obstacle which must be overcome, the delivery of a sufficient quantity of the substance through the stratum corneum to achieve a minimum effective concentration in the skin where peripheral opioid receptors, i.e. nerve tissue at the dermal/epidermal junction, are located. Applicants have further discovered that a third obstacle is maintaining a sufficient concentration of the active substance in the skin where peripheral opioid receptors are located for a minimum effective period of time to achieve the desired response. That is, it is not sufficient that a minimum concentration merely be reached; it must be sustained for a minimum time period.
It is Applicants"" unique discovery to have identified the limiting factors of concentration and duration of exposure and to have discovered formulations which penetrate into and through the stratum corneum and deliver the active substance to the skin where nerve tissue is located in sufficient quantity and duration.
The invention relates generally to loperamide hydrochloride compositions and methods for the use of loperamide hydrochloride compositions. Preferably, the compositions contain dissolved loperamide hydrochloride at a concentration of at least about 1% (w/w) of the composition. More preferably, the concentration of dissolved loperamide hydrochloride is greater than about 16% (w/w), even more preferably is at least about 20% (w/w), and most preferably is at least about 30% (w/w). Compositions preferably display an in vitro rate of penetration of loperamide hydrochloride through the stratum corneum is at least about 0.3 xcexcg per cm2 per hour, more preferably is at least about 0.3 xcexcg per cm2 per hour for one hour after administration, and most preferably is at least about 0.3 xcexcg per cm2 per hour for six hours after administration. Percent compositions of the various components in the inventive compositions are preferably determined at 22xc2x0 C.
A preferred embodiment is directed towards a composition comprising dissolved loperamide hydrochloride, propylene carbonate, and ethanol, wherein the concentration of dissolved loperamide hydrochloride is at least about 1% (w/w) of the composition. The composition preferably has an in vitro rate of penetration of loperamide hydrochloride through the stratum corneum is at least about 0.3 xcexcg per cm2 per hour, more preferably is at least about 0.3 xcexcg per cm2 per hour for one hour after administration, and most preferably is at least about 0.3 xcexcg per cm2 per hour for six hours after administration. The composition may further comprise a hydrotropic agent. The hydrotropic agent may generally be any hydrotropic agent which functions to increase disorder in the lamellar liquid crystalline structure of the stratum corneum and thus allow increased transdermal transport, and preferably is isopropyl alcohol, propylene glycol, or sodium xylene sulfonate. The composition may further comprise an opioid analgesic. The opioid analgesic may generally be any opioid analgesic, and preferably is morphine, heroin, hydromorphine, oxymorphine, levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, drocode, oxycodone, propoxyphene, buprenorphine, pentazocine, nalbuphine, or butorphanol. The composition may further comprise moisturizers, humectants, oils, emulsifiers, thickeners, thinners, surface active agents, fragrances, preservatives, antioxidants, vitamins, or minerals. The composition may further comprise a penetration enhancer effective to improve the percutaneous penetration of the loperamide hydrochloride into and through the stratum corneum with respect to a composition lacking the penetration enhancer. The penetration enhancer may generally be any penetration enhancer, preferably is oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, and more preferably is oleic acid or oleyl alcohol.
An alternative embodiment is directed towards a composition comprising dissolved loperamide hydrochloride, propylene glycol, and ethyl acetate, wherein the concentration of dissolved loperamide hydrochloride is at least about 1% (w/w) of the composition. The composition preferably has an in vitro rate of penetration of loperamide hydrochloride through the stratum corneum is at least about 0.3 xcexcg per cm2 per hour, more preferably is at least about 0.3 xcexcg per cm2 per hour for one hour after administration, and most preferably is at least about 0.3 xcexcg per cm2 per hour for six hours after administration. The composition may further comprise a hydrotropic agent. The hydrotropic agent may generally be any hydrotropic agent which functions to increase disorder in the lamellar liquid crystalline structure of the stratum corneum and thus allow increased transdermal transport, and preferably is isopropyl alcohol, propylene glycol, or sodium xylene sulfonate. The composition may further comprise an opioid analgesic. The opioid analgesic may generally be any opioid analgesic, and preferably is morphine, heroin, hydromorphine, oxymorphine, levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, drocode, oxycodone, propoxyphene, buprenorphine, pentazocine, nalbuphine, or butorphanol. The composition may further comprise moisturizers, humectants, oils, emulsifiers, thickeners, thinners, surface active agents, fragrances, preservatives, antioxidants, vitamins, or minerals. The composition may further comprise a penetration enhancer effective to improve the percutaneous penetration of the loperamide hydrochloride into and through the stratum corneum with respect to a composition lacking the penetration enhancer. The penetration enhancer may generally be any penetration enhancer, preferably is oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, and more preferably is oleic acid or oleyl alcohol.
An alternative embodiment is directed towards a composition comprising dissolved loperamide hydrochloride, N-methyl-2-pyrrolidone, and ethanol, wherein the concentration of dissolved loperamide hydrochloride is at least about 1% (w/w) of the composition. The composition preferably has an in vitro rate of penetration of loperamide hydrochloride through the stratum corneum is at least about 0.3 xcexcg per cm2 is 5 per hour, more preferably is at least about 0.3 xcexcg per cm2 per hour for one hour after administration, and most preferably is at least about 0.3 xcexcg per cm2 per hour for six hours after administration. The composition may further comprise a hydrotropic agent. The hydrotropic agent may generally be any hydrotropic agent which functions to increase disorder in the lamellar liquid crystalline structure of the stratum corneum and thus allow increased transdermal transport, and preferably is isopropyl alcohol, propylene glycol, or sodium xylene sulfonate. The composition may further comprise an opioid analgesic. The opioid analgesic may generally be any opioid analgesic, and preferably is morphine, heroin, hydromorphine, oxymorphine, levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, drocode, oxycodone, propoxyphene, buprenorphine, pentazocine, nalbuphine, or butorphanol. The composition may further comprise moisturizers, humectants, oils, emulsifiers, thickeners, thinners, surface active agents, fragrances, preservatives, antioxidants, vitamins, or minerals. The composition may further comprise water, or water and propylene glycol. The composition may further comprise a penetration enhancer effective to improve the percutaneous penetration of the loperamide hydrochloride into and through the stratum corneum with respect to a composition lacking the penetration enhancer. The penetration enhancer may generally be any penetration enhancer, preferably is oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, and more preferably is oleic acid or oleyl alcohol.
Preferred compositions contain propylene carbonate and ethanol or a blend of N-methyl-2-pyrrolidone, ethanol, and propylene glycol or water or the blend of N-methyl-2-pyrrolidone, ethanol, propylene glycol and water. For example, one composition may comprise between about 25% and about 70% ethanol or propylene carbonate, between about 25% and about 70% water, between about 1% and about 10% penetration enhancer and between about 1% and about 10% opioid analgesic, wherein the percentages total to 100%. Another composition may comprise between about 10% and about 70% ethanol, between about 10% and about 70% propylene carbonate, between about 1% and about 10% penetration enhancer, and between about 1 % and about 10% opioid analgesic wherein the percentages total to 100%. Two particularly preferred compositions are: (1) 10% N-methyl-2-pyrrolidone, 10% propylene glycol, 40% ethanol, 30% water, 5% loperamide hydrochloride, 5% enhancing, gelling, and preserving agents; and (2) 45% propylene carbonate, 45% ethanol, 5% loperamide hydrochloride, 5% gelling enhancing and preserving agents.
The invention is also directed towards methods for inducing analgesia or antihyperalgesia in mammals, humans, or non-human mammals, and preferably in humans. Alternatively, the invention is directed towards methods for inducing analgesia or antihyperalgesia in non-mammalian animals such as birds and amphibians. Commercially important birds such as chickens and turkeys may be potential subjects for the inventive compositions and methods.
An embodiment is directed towards a method of inducing analgesia or antihyperalgesia in humans or in human epidermis, comprising topically applying a composition to the skin in a dosage effective to cause analgesia or antihyperalgesia, wherein: the composition comprises dissolved loperamide hydrochloride, propylene carbonate, and ethanol; the concentration of dissolved loperamide hydrochloride is at least 1% (w/w) of the composition; and the composition has an in vitro rate of penetration of loperamide hydrochloride through the stratum corneum of at least about 0.3 xcexcg per cm2 per hour, more preferably is at least about 0.3 xcexcg per cm2 per hour for one hour after administration, and most preferably is at least about 0.3 xcexcg per cm2 per hour for six hours after administration. The composition may further comprise a hydrotropic agent. The hydrotropic agent may generally be any hydrotropic agent which functions to increase disorder in the lamellar liquid crystalline structure of the stratum corneum and thus allow increased transdermal transport, and preferably is isopropyl alcohol, propylene glycol, or sodium xylene sulfonate. The composition may further comprise an opioid analgesic. The opioid analgesic may generally be any opioid analgesic, and preferably is morphine, heroin, hydromorphine, oxymorphine, levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, drocode, oxycodone, propoxyphene, buprenorphine, pentazocine, nalbuphine, or butorphanol. The composition may further comprise moisturizers, humectants, oils, emulsifiers, thickeners, thinners, surface active agents, fragrances, preservatives, antioxidants, vitamins, or minerals. The composition may further comprise a penetration enhancer effective to improve the percutaneous penetration of the loperamide hydrochloride into and through the stratum corneum with respect to a composition lacking the penetration enhancer. The penetration enhancer may generally be any penetration enhancer, preferably is oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, and more preferably is oleic acid or oleyl alcohol.
An alternative embodiment is directed towards a method of inducing analgesia or antihyperalgesia in humans or in human epidermis, comprising topically applying a composition to the skin in a dosage effective to cause analgesia or antihyperalgesia, wherein: the composition comprises dissolved loperamide hydrochloride, propylene glycol, and ethyl acetate; the concentration of dissolved loperamide hydrochloride is at least 1% (w/w) of the composition; and the composition has an in vitro rate of penetration of loperamide hydrochloride through the stratum corneum of at least about 0.3 xcexcg per cm2 per hour, more preferably is at least about 0.3 xcexcg per cm2 per hour for one hour after administration, and most preferably is at least about 0.3 xcexcg per cm2 per hour for six hours after administration. The composition may further comprise a hydrotropic agent. The hydrotropic agent may generally be any hydrotropic agent which functions to increase disorder in the lamellar liquid crystalline structure of the stratum corneum and thus allow increased transdermal transport, and preferably is isopropyl alcohol, propylene glycol, or sodium xylene sulfonate. The composition may further comprise an opioid analgesic. The opioid analgesic may generally be any opioid analgesic, and preferably is morphine, heroin, hydromorphine, oxymorphine, levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, drocode, oxycodone, propoxyphene, buprenorphine, pentazocine, nalbuphine, or butorphanol. The composition may further comprise moisturizers, humectants, oils, emulsifiers, thickeners, thinners, surface active agents, fragrances, preservatives, antioxidants, vitamins, or minerals. The composition may further comprise a penetration enhancer effective to improve the percutaneous penetration of the loperamide hydrochloride into and through the stratum corneum with respect to a composition lacking the penetration enhancer. The penetration enhancer may generally be any penetration enhancer, preferably is oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, and more preferably is oleic acid or oleyl alcohol.
An alternative embodiment is directed towards a method of inducing analgesia or antihyperalgesia in humans or in human epidermis, comprising topically applying a composition to the skin in a dosage effective to cause analgesia or antihyperalgesia, wherein: the composition comprises dissolved loperamide hydrochloride, N-methyl-2-pyrrolidone, and ethanol; the concentration of dissolved loperamide hydrochloride is at least 1% (w/w) of the composition; and the composition has an in vitro rate of penetration of loperamide hydrochloride through the stratum corneum of at least about 0.3 xcexcg per cm2 per hour, more preferably is at least about 0.3 xcexcg per cm2 per hour for one hour after administration, and most preferably is at least about 0.3 xcexcg per cm2 per hour for six hours after administration. The composition may further comprise a hydrotropic agent. The hydrotropic agent may generally be any hydrotropic agent which functions to increase disorder in the lamellar liquid crystalline structure of the stratum corneum and thus allow increased transdermal transport, and preferably is isopropyl alcohol, propylene glycol, or sodium xylene sulfonate. The composition may further comprise an opioid analgesic. The opiold analgesic may generally be any opioid analgesic, and preferably is morphine, heroin, hydromorphine, oxymorphine, levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, drocode, oxycodone, propoxyphene, buprenorphine, pentazocine, nalbuphine, or butorphanol. The composition may further comprise moisturizers, humectants, oils, emulsifiers, thickeners, thinners, surface active agents, fragrances, preservatives, antioxidants, vitamins, or minerals. The composition may further comprise water, or water and propylene glycol. The composition may further comprise a penetration enhancer effective to improve the percutaneous penetration of the loperamide hydrochloride into and through the stratum corneum with respect to a composition lacking the penetration enhancer. The penetration enhancer may generally be any penetration enhancer, preferably is oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, and more preferably is oleic acid or oleyl alcohol.